CN1671397A - Combined Application of Alkyl Choline Phosphoric Acid and Antineoplastic Drugs - Google Patents

Abstract

The invention relates to the use of alkylphosphocholines in combination with antitumor medicaments for the treatment of benign and malignant oncoses in humans and animals. It is possible in this connection for the alkylphosphocholines to be employed in a combination according to the invention with one or a combination of various approved cytostatics. Preferred alkylphosphocholines are described by the Formula II.

Description

Combined Application of Alkyl Choline Phosphoric Acid and Antineoplastic Drugs

Alkylphosphocholines are a new class of organic compounds that exhibit various antitumor activities (M. Lohmeyer and R. Bittman; Antitumor ether lipids and alkylphosphocholines, DOF, 19 (11), 1021-1037 (1994)). The action of alkylphosphocholines in this regard may be based on different molecular and biochemical mechanisms, some of which occur at the level of the plasma membrane of the cell. Alkylcholine phosphates are known to affect inositol metabolism, interaction with phospholipases or inhibition of protein kinase C, thus such substances have general effects on cell signal transduction (K. Maly, F. berall, C Schubert, E. Kindler, J. Stekar, H. Brachwitz and HH Grunicke, Interference of new alkylphospholipid analogues with mitogenic signal transduction, Anti-Cancer Drug Design, 10 , 411-425 (1995)). Thus, perifosine alkylcholine phosphate exhibited growth inhibitory properties in relation to different melanoma, CNS, lung, colon, prostate and breast cancer cell lines with an _IC50 ranging from 0.2-20 μM (P.Hilgard , T.Klenner, J.Stekar, GNössner, B.kutscher and J.Engel; D-21266, a New Heterocyclic Alkylphospholipid with Antitumor Activity, Eur.J.Cancer, 33 (3), 442-446(1997)) . Perifosine is also known to block tumor cells in the G ₁ -S and G ₂ -M phases of the cell cycle (V. Patel, T. Lahusen, T. Sy, EASausville, JS Gutkind and AMSenderowicz; Perifosine, a Novel Alkylphospholipid, Induces p21 ^Waf1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest, Cancer Research 62 , 1401-1409 (2002)).

Alkyl-Lysophospholipids as Anticancer Agents and Enhancers of Radiation-Induced Apoptosis, Int. J. Radiation Oncology, are known to lead to synergistic effects in tumor therapy when administered prior to or together with radiation therapy (GARuitter, M. Verheijl, SF Zerp and WJ van Blitterswijk; Biol. Phys., 49(2), 415-420, 2001). It has also been reported that different glycerol-3-phospholipids, such as ET-18-OCH ₃ , in combination with different DNA interacting substances or tubulin binding agents increase the in vitro antitumor activity against different tumor cell lines (A. Noseda, ME Berens , JGWhite and EJModest; In vitroantiproliferative activity of combinations of ether lipidanalogs and DNA-Interactive agents against human tumor cells, Cancer Res., 48 (7), 1788-1791(1988); P.Principe, H.Coulomb, C.Broquet and P. Braquet; Evaluation of combinations of antineoplastic ether phospholipids and chemotherapeutic drugs, Ant-Cancer Drugs, 3(6), 577-587 (1992); P. Principe, H. Coulomb, J.-M. Mencia-Huerta, C . Broquet and P. Braquet; Synergistic cytotoxic effect of aza-alkylphospholipids inassociation with chemotherapeutic drugs, J. Lipid Mediators Cell Signaling, 10 (1-2), 171-173 (1994)).

It has now surprisingly been shown that the linear alkylphosphocholines of the general formulas I and II are suitable for use according to the invention in combination with other medicinal products for the treatment of benign and malignant neoplastic diseases in humans and mammals. In this connection it is possible according to the invention to use the compounds of the general formulas I and II in combination with antineoplastic substances. Antineoplastic substances may be agonists or antagonists of alkylating agents, antimetabolites, plant alkaloids, platinum compounds, tumor antibiotics and natural hormones. Anti-tumor substances can be selected from but not limited to: cisplatin, carboplatin, oxaliplatin, bleomycin, doxorubicin, methotrexate, paclitaxel, docetaxel, vincristine, vinblastine , etoposide, teniposide, ifosfamide, cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, and arabinoside.

Alkylphosphocholines of general formula I and II are more likely to be used in the proposed combination with signal transduction inhibitors in the form of high and low molecular weight receptor and/or cytoplasmic kinase inhibitors. These inhibitors can be selected from, but are not limited to, monoclonal antibodies and heterocyclic compounds. The alkylphosphocholines of the formulas I and II on which the present invention is based can be used in the form of finished pharmaceutical products.

The compounds on which the present invention is based are described by the general formulas I and II:

where, independently of each other:

n, m, p, z are integers of 0-4;

x is O, S, NH;

R is H, linear or branched (C ₁ -C ₂₀ )-alkyl, said group may be saturated or unsaturated with 1-3 double bonds and/or triple bonds, and may be unsubstituted or Optionally replaced by 1, 2 or more halogen, nitro, cyano, hydroxyl, (C ₁ -C ₆ )-alkoxy, amino, mono-(C ₁ -C ₄ )-alkylamino or di-(C ₁ -C ₄ )-alkylamino substitution;

R ₁ , R ₂ , R ₃ are independently of one another H, linear or branched (C ₁ -C ₆ )-alkyl, preferably methyl and ethyl, (C ₃ -C ₇ )-cycloalkyl, and It can be unsubstituted or optionally replaced by 1, 2 or more halogen, nitro, cyano, hydroxyl, (C ₁ -C ₆ )-alkoxy, amino, mono- (C1-C4)-Alkylamino or di-( _C1 - _C4 )-Alkylamino substitution.

According to another aspect of the present invention, there is provided a method of controlling tumors in humans and mammals, which comprises administering to humans or mammals a certain amount of at least one compound of general formulas I and II as the basis of the present invention to effectively Tumor therapy prior to or during treatment with approved antineoplastic substances.

The therapeutically effective dose of the specific compounds of the general formulas I and II on which the invention is based to be administered for treatment depends on the nature and stage of the neoplastic disease, the age and sex of the patient, the mode of administration and the duration of the treatment.

The compounds on which the present invention is based can be administered as pharmaceuticals in the form of liquid, semisolid and solid pharmaceuticals. Takes the following forms in a manner suitable for each case: aerosols, oral powders, dusting and dusting powders, uncoated tablets, coated tablets, emulsions, foams, solutions, suspensions, gels, ointments, Paste, pill, lozenge, capsule, or suppository.

Exemplary implementations:

1. Combination administration of perifosine (D-21 266) and cisplatin

In Vivo: DMBA-Induced Rat Breast Cancer Model

Experimental animals: Sprague-Dawley rats, female

method:

Induction of breast cancer by a single oral dose of DMBA. Animals received perifoxine on days 0 to 14 and were observed until day 42. Estimate the weight of the tumor mass by palpation and comparison with the plastic model. The initial weight is set to 100%.

Administration: Perifosine 14×6.81mg/kg p.o.

Cisplatin 4×1mg/kg i.p.

Effect:

The reduction in tumors was significantly greater and longer-lasting by the combination therapy than by the individual agents alone.

Treatment Tumor Day 21 p-Test vs. Control

Initial Weight [g] Change [%]

Control 1.0 875 -

Perifosine (D-21266) 0.9 -25 ＜0.001

Cisplatin 0.9 410 0.120

Perifosine (D-21266) 0.8 -75 ＜0.001

+cisplatin

2. Combination administration of perifosine and cyclophosphamide

In Vivo: DMBA-Induced Rat Breast Cancer Model

Experimental animals: Sprague-Dawley rats, female

method:

Induction of breast cancer by a single oral dose of DMBA. Animals received perifoxine on days 0 to 14 and were observed until day 42. Estimate the weight of the tumor mass by palpation and comparison with the plastic model. The initial weight is set to 100%.

Administration: Perifosine 14×6.81mg/kg p.o.

  Cyclophosphamide 100mg/kg, VZ 0, i.v.

Effect:

The reduction in tumors was significantly greater and longer-lasting by the combination therapy than by the individual agents alone.

Treatment Tumor Day 21 Relative to control p

Initial Weight [g] Change [%] Test

Control 1.0 875 -

Perifosine (D-21266) 0.9 -25 ＜0.001

Cyclophosphamide 0.9 500 0.011

Perifosine (D-21266) 0.8 -83.3 ＜0.001

+ Cyclophosphamide

3. Combined administration of perifosine and doxorubicin

In Vivo: DMBA-Induced Rat Breast Cancer Model

Experimental animals: Sprague-Dawley rats, female

method:

Induction of breast cancer by a single oral dose of DMBA. Animals received perifoxine on days 0 to 14 and were observed until day 42. Estimate the weight of the tumor mass by palpation and comparison with the plastic model. The initial weight is set to 100%.

Administration: Perifosine 14×6.81mg/kg p.o.

  Adriamycin 4×2.15mg/kg i.p.

Effect:

The reduction in tumors was significantly greater and longer-lasting by the combination therapy than by the individual agents alone.

Treatment Tumor Day 21 Relative to Control p

Initial Weight [g] Change [%] Test

Control 1.0 875 -

Perifosine (D-21266) 0.9 -25 ＜0.001

Adriamycin 1.0 781.3 0.197

Perifosine (D-21266) 0.10 -70 ＜0.001

+ Adriamycin

Claims (12)

1. the alkyl phosphoric acid choline of general formula I and II is used for the preparation of the application of the medicine of treating benign and malignant neoplastic disease before and/or during treatment with approved antitumor drug,

where, independently of each other: n, m, p, z are integers of 0-4; x is O, S, NH; R is H, linear or branched (C ₁ -C ₂₀ )-alkyl, said group may be saturated or unsaturated with 1-3 double bonds and/or triple bonds, and may be unsubstituted or Optionally replaced by 1, 2 or more halogen, nitro, cyano, hydroxyl, (C ₁ -C ₆ )-alkoxy, amino, mono-(C ₁ -C ₄ )-alkylamino or di-(C ₁ -C ₄ )-alkylamino substitution; R ₁ , R ₂ , R ₃ are independently of one another H, linear or branched (C ₁ -C ₆ )-alkyl, preferably methyl and ethyl, (C ₃ -C ₇ )-cycloalkyl, and It can be unsubstituted or optionally replaced by 1, 2 or more halogen, nitro, cyano, hydroxyl, (C ₁ -C ₆ )-alkoxy, amino, mono- (C ₁ -C ₄ )-alkylamino or di-(C ₁ -C ₄ )-alkylamino substitution. 2. the alkylcholine phosphoric acid of general formula I as claimed in claim 1 is used for the preparation of the application of the medicine for the treatment of benign and malignant neoplastic diseases before and/or during the treatment with approved antitumor drug, where, independently of each other: n is an integer 1 or 2; m is an integer 1; X is O; R is H or straight chain or branched chain (C ₁ -C ₁₇ )-alkyl, said group can be saturated or 1-3 double bond and/or triple bond unsaturated; R ₁ , R ₂ , R ₃ are independently H, linear or branched (C ₁ -C ₆ )-alkyl, preferably methyl and ethyl, (C ₃ -C ₇ )-cycloalkyl . 3. the alkylphosphoric acid choline of general formula II as claimed in claim 1 is used for the preparation of the application of the medicine that treats benign and malignant neoplastic diseases before and/or during the treatment with approved antitumor drug, where, independently of each other: m and p are integers 1; n and z are integers 2; X is O; R is H, linear or branched (C ₁ -C ₁₇ )-alkyl, said group may be saturated or unsaturated with 1-3 double bonds and/or triple bonds; R ₁ , R ₂ , R ₃ are independently H, linear or branched (C ₁ -C ₆ )-alkyl, preferably methyl and ethyl, (C ₃ -C ₇ )-cycloalkyl . 4. 1,1-dimethylpiperidino-4-yl octadecyl phosphate as claimed in claim 1 for the preparation of benign and malignant before and/or during treatment with approved antineoplastic agents Application of drugs for tumor diseases. 5. The application of the alkylphosphoric acid choline of general formula I and II as claimed in claims 1-4, wherein the approved antineoplastic drug can be alkylating agent, antimetabolite, plant alkaloid, platinum compound, tumor Agonists or antagonists of antibiotics and natural hormones. 6. The application as claimed in claim 5, wherein the antitumor drug can be cisplatin, cyclophosphamide or doxorubicin. 7. Use of the phosphoric acid alkylcholines of general formula I and II as claimed in claims 1-4, wherein the approved antineoplastic agents may be in the form of high and low molecular weight receptor kinases and/or cytoplasmic kinase inhibitors Signal transduction inhibitors. 8. The use as claimed in claim 7, wherein the inhibitor may be a monoclonal antibody or a heterocyclic compound. 9. Use of the phosphoric acid alkylcholines of general formula I and II as claimed in claims 1-8 in therapeutic doses effective for treatment prior to and/or during treatment with approved antineoplastic agents. 10. Use of the alkylphosphocholines of general formulas I and II as claimed in claims 1-9, wherein the approved antineoplastic drug is a combination of different cytostatic agents. 11. as claimed in claim 1-4 the application of the alkylphosphoric acid choline of formula I and II required for the preparation of the medicine for the treatment of benign and malignant neoplastic diseases before and/or during the treatment with approved antitumor drugs, wherein the In addition to the alkylphosphonic acid cholines of the formulas I and II, the pharmaceutical product also contains conventional pharmaceutically acceptable carriers, excipients and/or diluents. 12. A medicinal product comprising at least one alkylphosphorylcholine of the general formulas I and II, if appropriate, carriers and/or excipients, for use prior to treatment with approved antineoplastic agents and/or Or during the treatment of benign and malignant tumor diseases.